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Journal of Neuro-ophthalmology : the... Jun 2022The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to...
BACKGROUND
The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines.
METHODS
We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later.
RESULTS
The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing.
CONCLUSION
A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.
Topics: COVID-19; Cerebellar Ataxia; Clonazepam; Female; Humans; Immunoglobulin G; Methylprednisolone Hemisuccinate; Ocular Motility Disorders; Opsoclonus-Myoclonus Syndrome; RNA, Viral; Receptors, GABA-A; Rituximab; SARS-CoV-2
PubMed: 34974489
DOI: 10.1097/WNO.0000000000001498 -
Hearing Research Jun 2022The role of the mammalian auditory olivocochlear efferent system in hearing has long been the subject of debate. Its ability to protect against damaging noise exposure... (Review)
Review
The role of the mammalian auditory olivocochlear efferent system in hearing has long been the subject of debate. Its ability to protect against damaging noise exposure is clear, but whether or not this is the primary function of a system that evolved in the absence of industrial noise remains controversial. Here we review the behavioral consequences of olivocochlear activation and diminished olivocochlear function. Attempts to demonstrate a role for hearing in noise have yielded conflicting results in both animal and human studies. A role in selective attention to sounds in the presence of distractors, or attention to visual stimuli in the presence of competing auditory stimuli, has been established in animal models, but again behavioral studies in humans remain equivocal. Auditory processing deficits occur in models of congenital olivocochlear dysfunction, but these deficits likely reflect abnormal central auditory development rather than direct effects of olivocochlear feedback. Additional proposed roles in age-related hearing loss, tinnitus, hyperacusis, and binaural or spatial hearing, are intriguing, but require additional study. These behavioral studies almost exclusively focus on medial olivocochlear effects, and many relied on lesioning techniques that can have unspecific effects. The consequences of lateral olivocochlear and of corticofugal pathway activation for perception remain unknown. As new tools for targeted manipulation of olivocochlear neurons emerge, there is potential for a transformation of our understanding of the role of the olivocochlear system in behavior across species.
Topics: Acoustic Stimulation; Animals; Auditory Perception; Cochlea; Efferent Pathways; Hearing; Hyperacusis; Mammals; Noise; Olivary Nucleus
PubMed: 33674070
DOI: 10.1016/j.heares.2021.108207 -
International Journal of Molecular... Aug 2021Stress adaptation is of utmost importance for the maintenance of homeostasis and, therefore, of life itself. The prevalence of stress-related disorders is increasing,... (Review)
Review
Stress adaptation is of utmost importance for the maintenance of homeostasis and, therefore, of life itself. The prevalence of stress-related disorders is increasing, emphasizing the importance of exploratory research on stress adaptation. Two major regulatory pathways exist: the hypothalamic-pituitary-adrenocortical axis and the sympathetic adrenomedullary axis. They act in unison, ensured by the enormous bidirectional connection between their centers, the paraventricular nucleus of the hypothalamus (PVN), and the brainstem monoaminergic cell groups, respectively. PVN and especially their corticotropin-releasing hormone (CRH) producing neurons are considered to be the centrum of stress regulation. However, the brainstem seems to be equally important. Therefore, we aimed to summarize the present knowledge on the role of classical neurotransmitters of the brainstem (GABA, glutamate as well as serotonin, noradrenaline, adrenaline, and dopamine) in stress adaptation. Neuropeptides, including CRH, might be co-localized in the brainstem nuclei. Here we focused on CRH as its role in stress regulation is well-known and widely accepted and other CRH neurons scattered along the brain may also complement the function of the PVN. Although CRH-positive cells are present on some parts of the brainstem, sometimes even in comparable amounts as in the PVN, not much is known about their contribution to stress adaptation. Based on the role of the Barrington's nucleus in micturition and the inferior olivary complex in the regulation of fine motoric-as the main CRH-containing brainstem areas-we might assume that these areas regulate stress-induced urination and locomotion, respectively. Further studies are necessary for the field.
Topics: Adaptation, Physiological; Animals; Brain Stem; Corticotropin-Releasing Hormone; Humans; Neurons; Stress, Physiological
PubMed: 34445795
DOI: 10.3390/ijms22169090 -
Current Opinion in Physiology Dec 2020During development and adulthood, the normal activity of the auditory nerve plays a critical role in the maintenance of both fundamental structural, molecular, and...
During development and adulthood, the normal activity of the auditory nerve plays a critical role in the maintenance of both fundamental structural, molecular, and functional parameters of auditory nerve synapses, and the postsynaptic excitatory or inhibitory neurons within the cochlear nucleus (CN). In addition, normal activity within the synaptic circuits of the CN is key to developing and maintaining appropriate synapse connectivity as well as the initiation of binaural sound processing in the superior olivary complex (SOC). Development plays a critical role in the proper neuronal connectivity and establishes a topographic map along the entire auditory pathway. Furthermore, evidence shows that neurons and synaptic circuits in the auditory brainstem are not hard-wired, but instead are plastic in response to hearing deficits. Whether this plasticity in response to hearing loss is compensatory or pathological is still unknown.
PubMed: 33103017
DOI: 10.1016/j.cophys.2020.07.002 -
Acta Neuropathologica Oct 2023Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological...
Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71 years (53-82 years), the median disease duration was 6 years (0.5-13 years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9 years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25 years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients.
Topics: Aged; Female; Humans; Male; Autopsy; Encephalitis; Hashimoto Disease; Immunoglobulin G; Cell Adhesion Molecules, Neuronal; tau Proteins
PubMed: 37646790
DOI: 10.1007/s00401-023-02625-6 -
Frontiers in Neuroscience 2023The pathological involvement of the central nervous system in SARS-CoV2 (COVID-19) patients is established. The burden of pathology is most pronounced in the brain stem...
The pathological involvement of the central nervous system in SARS-CoV2 (COVID-19) patients is established. The burden of pathology is most pronounced in the brain stem including the medulla oblongata. Hypoxic/ischemic damage is the most frequent neuropathologic abnormality. Other neuropathologic features include neuronophagia, microglial nodules, and hallmarks of neurodegenerative diseases: astrogliosis and microglial reactivity. It is still unknown if these pathologies are secondary to hypoxia versus a combination of inflammatory response combined with hypoxia. It is also unknown how astrocytes react to neuroinflammation in COVID-19, especially considering evidence supporting the neurotoxicity of certain astrocytic phenotypes. This study aims to define the link between astrocytic and microglial pathology in COVID-19 victims in the inferior olivary nucleus, which is one of the most severely affected brain regions in COVID-19, and establish whether COVID-19 pathology is driven by hypoxic damage. Here, we conducted neuropathologic assessments and multiplex-immunofluorescence studies on the medulla oblongata of 18 COVID-19, 10 pre-pandemic patients who died of acute respiratory distress syndrome (ARDS), and 7-8 control patients with no ARDS or COVID-19. The comparison of ARDS and COVID-19 allows us to identify whether the pathology in COVID-19 can be explained by hypoxia alone, which is common to both conditions. Our results showed increased olivary astrogliosis in ARDS and COVID-19. However, microglial density and microglial reactivity were increased only in COVID-19, in a region-specific manner. Also, olivary hilar astrocytes increased YKL-40 (CHI3L1) in COVID-19, but to a lesser extent than ARDS astrocytes. COVID-19 astrocytes also showed lower levels of Aquaporin-4 (AQP4), and Metallothionein-3 in subsets of COVID-19 brain regions. Cluster analysis on immunohistochemical attributes of astrocytes and microglia identified ARDS and COVID-19 clusters with correlations to clinical history and disease course. Our results indicate that olivary glial pathology and neuroinflammation in the COVID-19 cannot be explained solely by hypoxia and suggest that failure of astrocytes to upregulate the anti-inflammatory YKL-40 may contribute to the neuroinflammation. Notwithstanding the limitations of retrospective studies in establishing causality, our experimental design cannot adequately control for factors external to our design. Perturbative studies are needed to confirm the role of the above-described astrocytic phenotypes in neuroinflammation.
PubMed: 37483351
DOI: 10.3389/fnins.2023.1198219 -
Neuroscience Insights 2021Hypertrophic olivary degeneration is a rare condition caused by a lesion in the Guillain-Mollaret triangle which leads to trans-synaptic degeneration resulting in the... (Review)
Review
Hypertrophic olivary degeneration is a rare condition caused by a lesion in the Guillain-Mollaret triangle which leads to trans-synaptic degeneration resulting in the degenerative hypertrophy of the inferior olivary nucleus. This condition presents clinically with palatal tremor but can also produce ocular myoclonus or cerebellar signs. While any lesion that occurs within the Guillian-Mollaret triangle and results in the deafferentation of the inferior olive can lead to hypertrophic olivary degeneration, the most common etiologies include ischemic and hemorrhagic stroke, vascular malformation, neoplasm, and iatrogenic injury related to surgery. We report a series of 7 patients who presented with this condition bilaterally on MRI imaging, including 1 case which represents the first report of toxoplasmosis leading to the development of bilateral hypertrophic olivary degeneration and only the third reported case, unilateral or bilateral, related to an infectious etiology.
PubMed: 34485912
DOI: 10.1177/26331055211007445 -
Hearing Research Nov 2022The cochlear efferent system comprises multiple populations of brainstem neurons whose axons project to the cochlea, and whose responses to acoustic stimuli lead to... (Review)
Review
The cochlear efferent system comprises multiple populations of brainstem neurons whose axons project to the cochlea, and whose responses to acoustic stimuli lead to regulation of auditory sensitivity. The major groups of efferent neurons are found in the superior olivary complex and are likely activated by neurons of the cochlear nucleus, thus forming a simple reflex pathway back to the cochlea. The peripheral actions of only one of these efferent cell types has been well described. Moreover, the efferent neurons are not well understood at the cellular- and circuit-levels. For example, ample demonstration of descending projections to efferent neurons raises the question of whether these additional inputs constitute a mechanism for modulation of relay function or instead play a more prominent role in driving the efferent response. Related to this is the question of synaptic plasticity at these synapses, which has the potential to differentially scale the degree of efferent activation across time, depending on the input pathway. This review will explore central nervous system aspects of the efferent system, the physiological properties of the neurons, their synaptic inputs, their modulation, and the effects of efferent axon collaterals within the brainstem.
Topics: Acoustic Stimulation; Auditory Pathways; Brain Stem; Cochlea; Cochlear Nucleus; Efferent Pathways; Neurons, Efferent; Olivary Nucleus
PubMed: 35606211
DOI: 10.1016/j.heares.2022.108516 -
Frontiers in Neurology 2022Hypertrophic olivary degeneration (HOD) is a pathology of the inferior olivary nucleus (ION) that occurs after injuries to the Guillain-Mollaret triangle (GMT). Lacking...
PURPOSE
Hypertrophic olivary degeneration (HOD) is a pathology of the inferior olivary nucleus (ION) that occurs after injuries to the Guillain-Mollaret triangle (GMT). Lacking a diagnostic gold standard, diagnosis is usually based on T2 or FLAIR imaging and expert rating. To facilitate precise HOD diagnosis in future studies, we assessed the reliability of this rater-based approach and explored alternative, quantitative analysis.
METHODS
Patients who had suffered strokes in the GMT and a matched control group prospectively underwent an MRI examination including T2, FLAIR, and proton density (PD). Diffusion tensor imaging (DTI) was additionally performed in the patient group. The presence of HOD was assessed on FLAIR, T2, and PD separately by 3 blinded reviewers. Employing an easily reproducible segmentation approach, relative differences in intensity, fractional anisotropy (FA), and mean diffusivity (MD) between both IONs were calculated.
RESULTS
In total, 15 patients were included in this study. The interrater reliability was best for FLAIR, followed by T2 and PD (Fleiss κ = 0.87 / 0.77 / 0.65). The 3 raters diagnosed HOD in 38-46% (FLAIR), 40-47% (T2), and 53-67% (PD) of patients. False-positive findings in the control group were less frequent in T2 than in PD and FLAIR (2.2% / 8.9% / 6.7%). In 53% of patients, the intensity difference between both IONs on PD was significantly increased in comparison with the control group. These patients also showed significantly decreased FA and increased MD.
CONCLUSION
While the rater-based approach yielded the best performance on T2 imaging, a quantitative, more sensitive HOD diagnosis based on ION intensities in PD and DTI imaging seems possible.
PubMed: 35989923
DOI: 10.3389/fneur.2022.950191